EP1898210A2 - Drucksteuerungssystem für mehrere Behälter - Google Patents

Drucksteuerungssystem für mehrere Behälter Download PDF

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Publication number
EP1898210A2
EP1898210A2 EP07018900A EP07018900A EP1898210A2 EP 1898210 A2 EP1898210 A2 EP 1898210A2 EP 07018900 A EP07018900 A EP 07018900A EP 07018900 A EP07018900 A EP 07018900A EP 1898210 A2 EP1898210 A2 EP 1898210A2
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EP
European Patent Office
Prior art keywords
pressure
channel
flow
microfluidic
network
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP07018900A
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English (en)
French (fr)
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EP1898210A3 (de
Inventor
Ring-Ling Chien
Wallace J. Parce
Andrea W. Chow
Anne Kopf-Sill
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Caliper Life Sciences Inc
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Caliper Life Sciences Inc
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Publication date
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Priority claimed from EP20010922248 external-priority patent/EP1272834B1/de
Publication of EP1898210A2 publication Critical patent/EP1898210A2/de
Publication of EP1898210A3 publication Critical patent/EP1898210A3/de
Withdrawn legal-status Critical Current

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    • G—PHYSICS
    • G05—CONTROLLING; REGULATING
    • G05D—SYSTEMS FOR CONTROLLING OR REGULATING NON-ELECTRIC VARIABLES
    • G05D7/00—Control of flow
    • G05D7/06—Control of flow characterised by the use of electric means
    • G05D7/0617—Control of flow characterised by the use of electric means specially adapted for fluid materials
    • G05D7/0629—Control of flow characterised by the use of electric means specially adapted for fluid materials characterised by the type of regulator means
    • G05D7/0694—Control of flow characterised by the use of electric means specially adapted for fluid materials characterised by the type of regulator means by action on throttling means or flow sources of very small size, e.g. microfluidics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/50273—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means or forces applied to move the fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00—Supporting devices; Holding devices
    • B01L9/52—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips
    • B01L9/527—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips for microfluidic devices, e.g. used for lab-on-a-chip
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/447—Systems using electrophoresis
    • G01N27/44756—Apparatus specially adapted therefor
    • G01N27/44791—Microapparatus
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/143—Quality control, feedback systems
    • B01L2200/146—Employing pressure sensors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N11/00—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties
    • G01N11/02—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties by measuring flow of the material
    • G01N11/04—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties by measuring flow of the material through a restricted passage, e.g. tube, aperture
    • G01N11/08—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties by measuring flow of the material through a restricted passage, e.g. tube, aperture by measuring pressure required to produce a known flow
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N2035/1027—General features of the devices
    • G01N2035/1034—Transferring microquantities of liquid
    • G01N2035/1044—Using pneumatic means

Definitions

  • the present invention is generally related to analytical tools for the biological and chemical sciences, and in particular, provides microfluidic devices, systems, and methods for selectively transporting fluids within microfluidic channels of a microfluidic network, often using a plurality of selectively variable pressures.
  • Electrokinetic forces have the advantages of direct control, fast response, and simplicity, and allow fluid materials to be selectively moved through a complex network of channels so as to provide a wide variety of chemical and biochemical, analyses.
  • An exemplary electrokinetic system providing variable control of electro-osmotic and/or electrophoretic forces within a fluid-containing structure is described in U.S. Patent No. 5,965,001 , the full disclosure of which is incorporated herein by reference.
  • electrokinetic material transport systems provide many benefits in the micro-scale movement, mixing, and aliquoting of fluids
  • the application of electrical fields can have detrimental effects in some instances.
  • electrical fields can cause electrophoretic biasing of material volumes, e.g., highly charged materials moving to the front or back of a fluid volume.
  • elevated electrical fields can, in some cases, result in a perforation or electroporation of the cells, which may effect their ultimate use in the system.
  • microfluidic devices, systems, and methods for selectively transporting fluids within one or more microfluidic channels of a microfluidic network It would be desirable if these improved transport techniques provided selective fluid movement capabilities similar to those of electrokinetic microfluidic systems, while mitigating the disadvantageous aspects of the application of electrical fields to chemical and biochemical fluids in at least some of the microfluidic channels of the network.
  • the invention also provides techniques to avoid fluid mixture degradation within a microfluidic channel by maintaining sufficient oscillation to avoid separation of the fluid mixture when no gross movement of the fluid is desired.
  • Microfluidic systems and methods having viscometers or other flow sensors are particularly useful for determining pressures so as to hydrodynamically induce a desire to flow in response to a measured flow within a microfluidic channel.
  • the techniques of the present invention may be used to provide feedback on!the actual flow and/or network system characteristics, allowing (for example) more accurate, stable and reliable assays.
  • the invention provides a microfluidic system comprising a body defining a microfluidic channel network and a plurality of reservoirs in fluid communication with the network.
  • the network includes a channel.
  • a plurality of pressure modulators are also included, each pressure modulator providing a selectably variable pressure.
  • a plurality of pressure transmission lumens transmit the pressures from the pressure modulators to the reservoirs so as to induce a desired flow within the channel.
  • the network will comprise a plurality of microfluidic channels in fluid communication at channel intersections.
  • the intersections and reservoirs will define nodes coupled by channel segments.
  • the network data can indicate correlations between the flows in the channel segments and the plurality of pressures.
  • a network data generator may be coupled to the network controller.
  • the network data generator may comprise a network flow model, a viscometer coupled to the channel, and/or a network tester adapted to measure at least one parameter indicating the pressure-flow correlation.
  • the pressure controller or controllers will often make use of signals from pressure sensors so as to provide a pressure feedback path.
  • the pressure controllers may include calibration data correlating drive signals with the resulting reservoir pressures.
  • the pressure modulators will comprise pneumatic displacement pumps.
  • At least one sample test liquid will be disposed in the channel network.
  • a pressure-transmission fluid can be disposed in the lumens, with a fluid/fluid-pressure-transmission interface disposed therebetween.
  • the pressure-transmission fluid will comprise a compressible gas, which can compliantly couple the pressure modulators with the channel flow.
  • the system will include at least four independently variable pressure modulators.
  • the system will make use of at least eight independently variable pressure modulators.
  • a pressure interface manifold can be used to releasably engage the microfluidic body, the manifold providing sealed fluid communication between the lumens and the associated reservoirs.
  • a plurality of electrodes will also be coupled to the microfluidic network with an electrokinetic controller coupled to the electrodes so as to induce electrokinetic movement of fluids within the network.
  • the pressure differential will be significantly greater than a capillary pressure of fluids within the reservoirs.
  • the invention provides a body defining a microfluidic channel network with a plurality of reservoirs in fluid communication with the network.
  • the network includes a first channel.
  • a plurality of pressure modulators is also provided, with each pressure modulator in fluid communication with a reservoir for varying a pressure applied thereto.
  • a network flow controller is coupled to the pressure modulators.
  • the network controller comprises channel network data correlating a flow within the first channel and the pressures from the pressure modulators.
  • the network controller independently varies the pressures from the pressure modulators in response to a desired flow within the first channel in the network data.
  • the system may further include means for generating the network data coupled to the network controller.
  • the network data generating means may comprise a model of the network, a viscometer, an electrical resistance sensor for sensing electrical resistance within the network, or the like.
  • the invention provides a microfluidic system comprising a body defining a microfluidic channel network and a plurality of ports in fluidic communication with the network.
  • the network includes a first channel.
  • a network flow controller generates independent desired pressure signals in response to a desired flow within the first channel.
  • a plurality of pressure modulators coupled to the network flow controller are each in fluid communication with an associated reservoir.
  • a pressure controller with calibration data couples the pressure modulators with the network controllers. The pressure controllers transmit drive signals to the pressure modulators in response to desired pressure signals from the network flow controller and the calibration data.
  • the invention provides a microfluidic method comprising transmitting a first plurality of pressures to an associated plurality of reservoirs using a plurality of pressure transmission systems.
  • a first flow is induced within a first microfluidic channel of a microfluidic network in response to the first pressures.
  • a second plurality of pressures in determined so as to effect a desired second flow within the first microfluidic channel.
  • the determined second plurality of pressures are applied with the pressure transmission systems and the second flow is induced within the first microfluidic channel with the second pressures.
  • the methods of the present invention are particularly well suited for precisely combining selected fluids within a microfluidic network, such,as for multiport dilution in which concentrations of first and second fluids from first and second reservoirs can be combined at different concentrations.
  • the invention provides a microfluidic method comprising determining pressure-induced flow characteristics of a microfluidic channel within a microfluidic network.
  • a first plurality of pressures are derived from the characteristics of the microfluidic network so as to provide a first desired flow in a first microfluidic channel.
  • the first desired flow is induced by applying the first pressures to a plurality of ports in communication with the microfluidic network.
  • the invention provides a method for use with a fluid mixture which can degrade when held stationary.
  • the method comprises introducing the fluid mixture into a microfluidic channel of a microfluidic network.
  • the mixture is maintained by oscillating the fluid mixture within the channel.
  • the maintained fluid mixture is then transported along the channel.
  • the invention provides a microfluidic method comprising inducing flow within a microfluidic channel of a microfluidic network.
  • the flow is measured and a pressure is calculated from the measured flow so as to generate a desired flow.
  • the desired flow is generated within the channel by applying the calculated pressure to the microfluidic network.
  • the flow is optionally measured by generating a detectable signal within the flow at a first location, and by measuring a time for the signal to reach a second location.
  • the signal may comprise a change in a fluid of the flow, particularly where the first location comprises an intersection between a plurality of microfluidic channels. Such a change in the flow may be initiated hydrodynamically by applying a pressure pulse to a reservoir in communication with the intersection, and/or electrokinetically by varying an electrical field across the first intersection.
  • a plurality of detectable signals from a plurality of channel intersections may be sensed as each of these signals reaches the second location.
  • a signal will comprise a change in an optical quality of fluid in the flow.
  • the signal may comprise a change in a concentration of a dye from a channel intersection, as described above.
  • the fluid comprises a photobleachable dye
  • the dye may be photobleached by a laser at the first location with the photobleaching sensed at the second location.
  • the speed of the flow may be determined by, for example, Dopler velocimetry, tracer particle videography, or the like.
  • a viscosity of the flow can be calculated using a first pressure (which induces the measured flow) and the speed of the flow. This viscosity can then be used in determination of the calculated pressure so as to generated the desired flow.
  • the invention provides a microfluidic system comprising a body defining a microfluidic channel network and a plurality of reservoirs in fluid communication with the network.
  • the network includes a microfluidic channel.
  • a viscometer is coupled to the channel for determining a viscosity of a flow therein.
  • the invention provides a microfluidic system comprising a body defining a microfluidic channel network and a plurality of reservoirs in fluid communication with the network.
  • the network includes a microfluidic channel.
  • a plurality of pressure modulators are in fluid communication with the reservoirs.
  • a sensor is coupled to the channel for transmission of flow signals in response to flow within the channel.
  • the controller couples the sensor to the pressure modulators.
  • the controller transmits pressure commands in response to the flow signals to provide a desired flow.
  • the invention provides a microfluidic system comprising a body defining a microfluidic channel network and a plurality of reservoirs in fluid communication with the network.
  • the system also includes means for selectively and independently varying pressures within the reservoirs.
  • the pressure varying means is in fluid communication with the reservoirs.
  • the invention provides a microfluidic method comprising inducing a perturbation in a flow through a microfluidic channel of a microfluidic network by applying a pressure transient to the microfluidic network.
  • a characteristic of the flow or microfluidic network is determined by monitoring progress of the perturbation.
  • pressure induced flow perturbations may be used to determine flow or network characteristics in systems having flow that is pressure induced, electrically induced, or any mixture of flow inducing mechanisms.
  • flow characteristics such as effective flow viscosity, flow speed, and the like may be determined.
  • network characteristics such as flow resistance of one or more channels may be determined.
  • the progress of the perturbation may be monitored at least in part with a sensor disposed downstream of a perturbation source location (such an intersection of channels).
  • a speed of the flow may be determined from, for example, a time interval extending from the pressure transient to detection of the perturbation at the sensor location, and from a distance along the channel or channels extending from the source location to the sensor location. More complex analyses are also possible, such as determining a second speed of a second flow. This second speed may be generated in response to a time interval defined in part by detection of a second flow perturbation, and a second distance defined in part by a second perturbation source location (such as a second channel intersection). As the different speeds along intersecting channels may be determined, the amount of materials combined from different channels at an intersection may be calculated.
  • the invention provides a microfluidic system comprising a body having channel walls defining a microfluidic network.
  • a pressure transient generator is in communication with a channel intersection of the microfluidic network for initiation of a flow perturbation.
  • a sensor is coupled to the flow within the network at a sensor location.
  • a processor coupled to the pressure generator and the sensor determines a characteristic of the flow or the network in response to detection of the perturbation at the sensor location.
  • Fig. 1 schematically illustrates a microfluidic system having a multi-reservoir pressure modulation system according to the principles of the present invention.
  • Figs. 3A and 3B are perspective views of a pressure manifold for releasably sealing reservoirs of the microfluidic device of channel 2 in fluid communication with the pressure modulators of the system of Fig. 1.
  • Fig. 4 schematically illustrates a control system for independently varying reservoir pressures in the microfluidic system of Fig. 1.
  • Figs. 5A-C schematically illustrate a method and computer program for determining pressures to provide a desired flow within a channel of the microfluidic network in the microfluidic device of Fig. 2.
  • Fig. 6 schematically illustrates a microfluidic system having both a multi-reservoir pressure modulation system and an electrokinetic fluid transportation and control system according to the principles of the present invention.
  • Figs. 7A and 7B illustrate well-pair dilution in which concentration variations are produced by selectively varying the relative flow rates from two reservoirs connected at an intersection.
  • Figs. 7C-E graphically illustrate measured dilution verses,set or intended dilution for a multi-reservoir pressure controlled well-pair dilution.
  • Figs. 8 and 8A-8D graphically illustrate an enzyme assay using a multi-reservoir pressure controlled microfluidic system, and more specifically: Fig. 8 illustrates the reaction, Fig. 8A is a titration curve for different substrate concentrations, Fig. 8B is a plot of the corrected signal verses substrate concentration, Fig. 8C is a plot for determination of the Michaelis constant, and Fig. 8D is a substrate titration plot.
  • Figs. 10A and 10B illustrate a mobility shift assay microfluidic network and assay test results at different concentrations.
  • Figs. 11A and 11B are a perspective and plane view, respectively, of an exemplary hydrodynamic and electrokinetic interface structure for coupling to a microfluidic body.
  • Fig. 12 schematically illustrates an exemplary microfluidic viscometer.
  • Figs. 13A and 13B schematically illustrate a microfluidic network and method for imposing detectable signals on a microfluidic flow for measurement of flow characteristics which can be used to calculate pressures to affect a desired flow.
  • Fig. 16 is a top view of a simple microfluidic chip having a single capillary for spontaneous injection.
  • Figs. 17A and 17B are perspective and plan view of fluorogenic multi-capillary chips.
  • Figs. 18A and 18B are perspective and plan view of a mobility-shift capillary chip.
  • Fig. 19 graphically illustrates the detection of a perturbation generated at an intersection of microfluidic channels by spontaneous injection.
  • pressure-induced microfluidic flows may, through proper chip design, reduce flow variabilities as compared to electrokinetic techniques through the use of pressure differentials (and/or channel resistances that are significantly greater than flow variations induced by secondary effects, such as inflow/outflow capillary force differentials within the reservoirs).
  • the pressure-induced flows of the present invention may also be combined with electrokinetic and/or other fluid transportation mechanisms thereby providing composite pressure/electrokinetic microfluidic systems.
  • the techniques of the present invention will often make use of data regarding the network of channels within a microfluidic device.
  • This network data may be calculated using a model of the microfluidic network, measured by testing a microfluidic device, sensed using a sensor, and/or the like.
  • the network data will often be in the form of hydrostatic resistances along microfluidic channel segments connecting nodes, with the nodes often being intersections between channels, ports or reservoirs, connections between channel segments having differing cross-sectional dimensions and/or flow characteristics, and the like.
  • the term "reservoir” encompasses ports for interfacing with a microfluidic network within a microfluidic body, including ports which do not have cross-sections that are much larger than the microfluidic channel to enhance fluid capacity.
  • the present invention may provide flow rates of less than 0.1 nanoliters per second, the flow rates often being less than 1 nanoliters per second, and the pressure induced flow rates typically being less than 10 nanoliters per second within the microfluidic channel.
  • the invention generally makes use of a pressure transmission system having relatively large lumens coupling the pressure modulators to the reservoirs of the microfluidic device, with the pressure transmission lumens ideally containing a compressible gas. Pressure is often transmitted through this relatively low resistance pressure transmission system to fluids disposed within the reservoirs of the microfluidic system via a gas/fluid interface within the reservoir.
  • the resistance of the microfluidic channels to the fluid flows therein is typically much greater than the resistance of the pressure transmission lumens to the associated flow of compressible gas.
  • the channel resistance is at least 10 times the transmission system resistance, preferably being at least 100 times, and ideally being at least 1000 times the transmission system resistance of the compressible gas used to induce the channel flows.
  • a response time constant of the pressure transmission system will generally be lower than the time constant of the channel network, preferably being much lower, and ideally being at least one, two, or three orders of magnitude lower.
  • the head space of a fluid (for example, in the pressure modulator pump and/or in the port or reservoir) times the resistance of the fluid flow (for example, in the channels or lumens) may generally define the response time constant.
  • the channels may have reduced cross-sectional dimensions, pressure drop members (such as a small cross-section pressure orifice, a flow restricting substance or coating, or the like), and/or lengths of some, most, or even all of the microfluidic channel segments may be increased by including serpentine segment paths.
  • pressure differentials can be accurately transmitted from the pressure modulators to the reservoirs of the microfluidic device. Additionally, reduced transmission system resistances can help to enhance the response of the pressure system, providing a faster response time constant.
  • a microfluidic system 10 includes a microfluidic device 12 coupled to a bank of pressure modulators 14 by a pressure transmission system 16.
  • Pressure modulator bank 14 includes a plurality of pressure modulators 14a, 14b, ...
  • Modulator bank 14 will generally include at least three independently, selectively variable pressure modulators, typically having at least four modulators, and ideally having eight or more modulators.
  • Each modulator is in fluid communication with a reservoir 18 of microfluidic device 12 via an associated tube 20, the tube having a pressure transmission lumen with a compressible gas therein.
  • Modulator bank 14 generally provides independently selectable pressures to the lumens of tubing 20 under the direction of a controller(s) 22. Feedback may be provided to controller 22 from pressure sensors 24, as will be described hereinbelow.
  • Processor 22 will often comprise a machine-readable code embodied by a tangible media 26, with the machine-readable code comprising program instructions and/or data for effecting the methods of the present invention.
  • Processor 22 may comprise a personal computer having at least an Intel Pentium ® or Pentium II ® processor having a speed of at least 200 MHz, 300 MHz, or more.
  • Tangible media 26 may comprise one or more floppy disks, compact disks, or "CDs," magnetic recording tape, a read-only memory, a random access memory, or the like.
  • pressure transmission system 16 includes a manifold 28.
  • Manifold 28 releasably seals the lumen of each tube 20 with an associated reservoir 18 of microfluidic device 12.
  • Tubing 20 may comprise a relatively high-strength polymer such as polyetheretherketone (PEEK), or a polytetrafluoroethylene (such as a TeflonTM material), or the like.
  • PEEK polyetheretherketone
  • TeflonTM material such as TeflonTM material
  • the tubing typically has an inner diameter in a range from about 0.01" to about 0.05", with a length from about 1m to about 3m.
  • a "T" connector couples the pressure output from each pressure modulator to an associated pressure sensor 24.
  • Microfluidic device 12 is seen more clearly in Fig. 2.
  • Microfluidic device 12 includes an array of reservoirs 18a, 18b, ... coupled together by microscale channels defining a microfluidic network 30.
  • microscale or “microfabricated” generally refers to structural elements or features of a device which have at least one fabricated dimension in the range of from about 0.1 ⁇ m to about 500 ⁇ m.
  • a device referred to as being microfabricated or microscale will include at least one structural element or feature having such a dimension.
  • microscale When used to describe a fluidic element, such as a passage, chamber or conduit, the terms “microscale”, “microfabricated” or “microfluidic” generally refer to one or more fluid passages, chambers or conduits which have at least one internal cross-sectional dimension, e.g., depth, width, length, diameter, etc., that is less than 500 ⁇ m, and typically between about 0.1 ⁇ m and about 500 ⁇ m.
  • the microscale channels or chambers preferably have at least one cross-sectional dimension between about 0.1 ⁇ m and 200 ⁇ m, more preferably between about 0.1 ⁇ m and 100 ⁇ m, and often between about 0.1 ⁇ m and 50 ⁇ m.
  • microfluidic devices or systems of the present invention typically include at least one microscale channel, usually at least two intersecting microscale channel segments, and often, three or more intersecting channel segments disposed within a single body structure.
  • Channel intersections may exist in a number of formats, including cross intersections, "T" intersections, or any number of other structures whereby two channels are in fluid communication.
  • the body structures of the devices which integrate various microfluidic channels, chambers or other elements may be fabricated from a number of individual parts, which when connected form the integrated microfluidic devices described herein.
  • the body structure can be fabricated from a number of separate capillary elements, microscale chambers, and the like, all of which are connected together to define an integrated body structure.
  • the integrated body structure is fabricated from two or more substrate layers which are mated together to define a body structure having the channel and chamber networks of the devices within.
  • a desired channel network is laid out upon a typically planar surface of at least one of the two substrate layers as a series of grooves or indentations in that surface.
  • a second substrate layer is overlaid and bonded to the first substrate layer, covering and sealing the grooves, to define the channels within the interior of the device.
  • a series of reservoirs or reservoirs is typically provided in at least one of the substrate layers, which reservoirs or reservoirs are in fluid communication with the various channels of the device.
  • silica-based substrates i.e., glass, quartz, fused silica, silicon and the like
  • polymeric substrates i.e., acrylics (e.g., polymethylmethacrylate) polycarbonate, polypropylene, polystyrene, and the like.
  • acrylics e.g., polymethylmethacrylate
  • polypropylene polypropylene
  • polystyrene polystyrene
  • preferred polymeric substrates are described in commonly owned published international patent application no. WO 98/46438 which is incorporated herein by reference for all purposes.
  • Silica-based substrates are generally amenable to microfabrication techniques that are well-known in the art including, e.g., photolithographic techniques, wet chemical etching, reactive ion etching (RJE) and the like.
  • Fabrication of polymeric substrates is generally carried out using known polymer fabrication methods, e.g., injection molding, embossing, or the like.
  • master molds or stamps are optionally created from solid substrates, such as glass, silicon, nickel electro forms, and the like, using well-known micro fabrication techniques. These techniques include photolithography followed by wet chemical etching, LIGA methods, laser ablation, thin film deposition technologies, chemical vapor deposition, and the like. These masters are then used to injection mold, cast or emboss the channel structures in the planar surface of the first substrate surface. In particularly preferred aspects, the channel or chamber structures are embossed in the planar surface of.the first substrate.
  • Methods of fabricating and bonding polymeric substrates are described in commonly owned U.S. Patent Application No. 09/073,710, filed May 6,1998 , and incorporated herein by reference in its entirety for all purposes.
  • reservoirs 18 will often be defined by openings in an overlaying substrate layer. Reservoirs 18 are coupled together by channels 32 of microfluidic network 30, with the channels generally being defined by indentations in an underlying layer of the substrate, as was also described above.
  • Microfluidic channels 32 are in fluid communication with each other at channel intersections 34a, 34b, ... (generally referred to as intersections 34). To simplify analysis of microfluidic network 30, channels 32 may be analyzed as channel segments extending between nodes defined at reservoirs 18 and/or channel intersections 34.
  • the resistance of channels 32 to flow through the microfluidic network may be enhanced.
  • These enhanced channel resistances may be provided by having a channel length greater than the normal separation between the nodes defining the channel segment, such as by having serpentine areas 36 along the channel segments.
  • a cross-sectional dimension of the channel may be decreased along at least a portion of the channel, or flow may be blocked by a flow restrictor such as a local orifice, a coating or material disposed in the channel, or the like.
  • Manifold 28 can be seen more clearly in Figs. 3A and 3B.
  • Manifold 28 has at least one device engaging surface 40 for engaging microfluidic device 12, with the engagement surface having an array of pressure lumens 42 corresponding to reservoirs 18 of the device.
  • Each of pressure lumens 42 is in fluid communication with a fitting 44 for coupling each reservoir with an associated pressure modulator via an associated tube.
  • Sealing body 46 helps maintain a seal between the associated pressure modulator and reservoir, and manifold 28 is releasably secured to device 12 by a securing mechanism 48, which here includes openings for threaded fasteners, or the like.
  • Manifold 28 may comprise a polymer, a metal such as 6061-T6 aluminum, or a wide variety of alternative materials.
  • Lumens 42 may have a dimension in a range from about 2 mm to about 3 mm.
  • Fittings 44 optionally comprise standard 1 ⁇ 4-28 fittings.
  • Sealing body 46 will often comprise an elastomer such as a natural or synthetic rubber.
  • the system will preferably be capable of varying pressure at reservoirs 18 throughout a range of at least 1 ⁇ 2 psi, more often having a pressure range of at least 1 psi, and most often having a pressure range of at least +/- 1 psig (so as to provide a 2 psi pressure differential.)
  • Many systems will be capable of applying at least about a 5 psi pressure differential, optionally having pressure transmission capabilities so as to apply pressure anywhere throughout a range of at least about +/- 5 psig.
  • Controller 22 generally includes circuitry and/or programming which allows the controller to determine reservoir pressures which will provide a desired flow within a channel of microfluidic network 30 (here schematically illustrated as microfluidic network controller 52) and also includes circuitry and/or programming to direct the modulators of modulator bank 14 to provide the desired individual reservoir pressures (here schematically illustrated as a plurality of pressure controllers 54.)
  • network controller 52 and pressure controller 54 may be integrated within a single hardware and/or software system, for example, running on a single processor board, or that a wide variety of distributing process techniques might be employed.
  • pressure controllers 54 are schematically illustrated here as separate pressure controllers for each modulator, a single pressure controller might be used with data sampling and/or multiplexing techniques.
  • pressure controller 54 transmits drive signals to an actuator 56, and the actuator moves a piston of displacement pump or syringe 58 in response to the drive signals. Movement of the piston within pump 58 changes a pressure in pressure transmission system 20, and the change in pressure is sensed by pressure sensor 24. Pressure sensor 24 provides a feedback signal to the pressure controller 54, and the pressure controller will optionally make use of the feedback signal so as to tailor the drive signals and accurately position the piston.
  • pressure controller 54 may include pressure calibration data 60.
  • the calibration data will generally indicate a correlation between drive signals transmitted to actuator 56 and the pressure provided from the pressure modulator.
  • Pressure calibration data 60 will preferably be determined by initially calibrating the pressure change system, ideally before initiation of testing using the microfluidic network.
  • calibration data 60 may be effected by transmitting a calibration drive signal to actuator 56 and sensing the pressure response using pressure sensor 24.
  • the change of pressure from this calibration test may be stored in the program as calibration data 60.
  • the calibration signal will typically cause a known displacement of the piston within pump 58.
  • Calibration may be preformed for each modulator/pressure transmission systems/reservoir (so as to accommodate varying reagent quantities within the reservoirs, and the like), or may be preformed on a single reservoir pressurization system as an estimate for calibration for all of the modulators of the system.
  • pressure controller 54 can generate drive signals for actuator 56 quite quickly in response to a desired pressure signal transmitted from network controller 52. It should be noted that these estimate will preferably accommodate the changing overall volume of the compressible gas within the system, so that the calculated change in pressure for a given displacement of the piston within pump 58 at low pressures may be different than the same displacement of the piston at high pressures (i.e., the displacement/pressure correlation plot is not linear, but curves.)
  • actuator 56 comprises a stepper motor coupled to a linear output mechanism.
  • Pump 58 comprises a syringe having a length of about 100 mm, and a diameter of about 20 mm.
  • Overall response time for the system may depend on a variety of parameters, including dead volume, syringe size, and the like.
  • the response time will be less than about 1 sec/psi of pressure change, ideally being less than about 500 msecs/psi for a pressure change from zero to 1 psi.
  • Network controller 52 generally calculates the desired pressure from each pressure modulator in response to a desired flow in one or more of the channels of microfluidic network 30. Given a desired channel flow, network controller 52 derives these pressures using network data 62, with the network data typically being supplied by either a mathematical model of the microfluidic network 64 and/or a tester 66. Network data 62 will generally indicate a correlation between pressure differentials applied to reservoirs 18 and flows within the microfluidic channels.
  • nodes can be defined at each well 18 and at each intersection 34.
  • Hydrodynamic resistances of channel segments coupling the nodes can be calculated from the chip design. More specifically, calculation of hydrodynamic resistances may be preformed using hydrostatic pressure loss calculations based on the cross sectional dimensions of channels 32, the length of channel segments connecting the nodes, the channel surface properties, the fluid properties of the fluids included in the flows, and the like.
  • Analysis of the multi-level flow resistance network may be performed using techniques often used for analysis of current in electrical circuits, as can be understood with reference to Figs. 5B-5C.
  • Hydrodynamic resistances of the channel segments connecting reservoirs 18 to adj acent nodes may be analyzed as the lowest level of a multi-level network.
  • the channel segments adjoining these lowest level segments form the second level of hydrodynamic resistances of the network.
  • This level-by-level analysis continues until all channels of microfluidic network 30 are included in the network model.
  • the relative flow rate of any channel in the microfluidic network can then be obtained once the flow rates from each of the reservoirs 18 in the lowest level have been calculated.
  • Figs. 7A and 7B One particular advantageous use of the pressure modulated flow control can be understood with reference to Figs. 7A and 7B.
  • Fig. 7A it is possible to vary the flows from two reservoirs electrokinetically, with the relative fluid concentrations being indicated by the changes in fluorescence intensity over time.
  • control over the relative flow rates (and hence, the concentration) may be less than ideal due to variation in capillary forces within the reservoirs and the like.
  • Fig. 7C is a plot of measured dilution vs. set dilution for a dilution well-pair with a hydrodynamic flow system, showing the accuracy and controllability of these dilution methods.
  • Figs. 7D and 7E are plots of the measured dilution near the upper and lower extremes, respectively, showing that a small amount of mixing at a channel intersection may occur when flow from a channel is at least substantially halted.
  • some modification of the overall flow from one or more channels at an intersection may be used to effect a desired dilution percentage adjacent a maximum and/or a minimum of the dilution range.
  • relative flow adjustments within 5% of a maximum or minimum desired dilution, and often within 2.5% of a desired maximum and/or minimum may be employed. More specifically, to achieve a near 0% actual dilution from a given channel at an intersection, fluid may flow into the channel at the intersection. Similarly, to achieve 100% measured dilution from the channel, more than 100% of the desired flow may be provided from the supply channel into the intersection.
  • Fig. 8A is a titration curve for different concentrations with and without substrate.
  • Fig. 8B A plot of background corrected signal vs. substrate concentration is shown in Fig. 8B, while a Lineweaver-Burk plot for the Michaelis constant (Km) is provided in Fig. 8C.
  • Results of a substrate titration assay for the reaction are shown in Fig. 8D.
  • exemplary manifold or chip interface structure 92' is illustrated in more detail.
  • Exemplary manifold 92' is adapted to provide both hydrodynamic coupling and electrokinetic coupling between a microfluidic body and an associated controller, as described above.
  • Electrical conduit passages 140 for coupling electrodes 94 to a system controller 22 (see Fig. 6) are illustrated in Fig. 11A.
  • Fig. 11B illustrates manifold pressure transmission lumens 142 which provide fluid communication between fittings 44 and a microfluidic body interface surface 144 within manifold 92'.
  • Manifold lumens 142 are illustrated in phantom.
  • a relatively simple flow sensor can be provided to measure an actual flow within a channel of a microfluidic network. Where the measured flow results from a known driving force (such as a known pressure differential) can be determined, pressures to be applied at the fluid reservoirs so as to affect a desired flow condition may then be calculated.
  • a known driving force such as a known pressure differential
  • Detector 154 is downstream from intersection 152, and can be used to detect the arrival time of the signal, for example, as a peak or dip in the intensity of a fluorescent signal from the dye.
  • the time difference between imposition of the signal at intersection 152 and sensing of the signal flow at detector 154 may be readily measured.
  • the steady-state flow with a constant pressure differential will result in a volumetric flow rate Q in channel 32 which is linearly proportional to the pressure differential ⁇ P and inversely proportional to the fluid viscosity ⁇ as follows:
  • Q K ⁇ P / ⁇ K is a proportionality constant which depends on the geometry of the channel network. K can be calculated from the channel geometry, or can be determined through a calibration standard test, or the like.
  • a variety of alternative structures may be used to sense flow characteristics so as to apply a proper pressure configuration to generate a desired flow.
  • a signal may be imposed on a flow within a micro fluidic channel by photobleaching of a fluorescent dye, rather than imposing a flow perturbation at a intersection.
  • Alternative flow velocimetry approaches such as laser Dopler velocimetry, tracer particle videography, and the like are also possible. Using such techniques, a simple straight channel connecting a fluid supply reservoir and a waste fluid reservoir may suffice, with the fluid supply reservoir containing a fluid comprising a photobleachable fluorescent tracer dye or appropriate tracer particles.
  • sensors may also be used to determine alternative flow characteristics within a microfluidic channel, including flow rate, viscosity, the proportionality constant for a segment or network (by use of fluids having known and/or uniform viscosities) and/or other flow characteristics.
  • flow rate a measure of flow rate
  • viscosity a measure of viscosity
  • the proportionality constant for a segment or network by use of fluids having known and/or uniform viscosities
  • other flow characteristics in addition to providing a tool to study effective viscosity of two or more mixed fluids (of optionally unequal viscosity) still further measurements are possible.
  • Mixing of DMSO and an acquiesce buffer can yield a non-monotonic viscosity-composition relationship.
  • viscometer 150 By applying different levels of pressure differential ⁇ P and measuring the flow rate Q , viscometer 150 could be used to establish a relationship of the effective viscosity during mixing as a function of mixing length. This information may be pertinent to chip design for tests which involve geometric dilution.
  • systems such as viscometer 150 can be coupled to a temperature control system comprising an external heater block in contact with the body defining the microfluidic channel network, by using joule heating to selectively control the temperature of fluids within the channel network, or the like.
  • a structure similar to viscometer 150 might be used to measure non-Newtonian viscosity.
  • Non-Newtonian fluids have viscosities which are a function of the sheer rate experienced by the fluid.
  • a non-Newtonian fluid is a polymer solution containing high molecular weight molecules.
  • a microfluidic viscometer similar to viscometer 150 of Fig. 12 might have a channel geometry and/or channel network intersection structure and/or flow arranged so that the application of a pressure differential creates a range of sheer stresses so as to accurately measure such non-Newtonian viscosity.
  • a steady flow can be directed toward reservoir 18a by applying initial pressures on wells 18.
  • a short pressure pulse may be applied to well 18e and/or some or all of the other reservoirs of the microfluidic system. This pressure pulse will propagate substantially instantly to alter flow at some or all of the intersections 34 of network 30. This disturbance of the flow at the node points can change the dilution ratio from one or more of the side branches. After the pressure pulse, steady state flow is resumed.
  • a time series of signals 160a, 160b, and 160c occur at times T 1 , T 2 , and T 3 , respectively.
  • the flow rate from some or all of the side branches may then be obtained from the difference of flow rates between successive node points.
  • the resistances of the branch channels may then be calculated. From the known channel geometry, the viscosity of the solution in the side branches may also be determined. This information can then be fed back to the network model to derive the pressures for a desired flow rate from each reservoir.
  • exemplary time signature data indicates that pressure pulse signals can effectively be imposed on the flow within a microfluidic system, and can accurately and repeatedly be sensed by a detector (such as an optical detector, or the like) for measurement of flow characteristics.
  • a detector such as an optical detector, or the like
  • halting movement of some fluid mixtures within a microfluidic network may have significant disadvantages. Specifically, cell-based assays performed using a fluid mixture including cells suspended in a liquid are susceptible to sticking of the cells to the channel walls if flow is completely halted. Similarly, other fluids may deteriorate if flow within the channel is sufficiently low for a sufficient amount of time.
  • the present invention can provide a small amplitude oscillatory movement of a fluid mixture so as to maintain the fluid mixture within a microfluidic channel.
  • Modulator bank 14 is capable of providing a small amplitude oscillatory pressure such that there is no significant inflow or outflow of materials from the channel.
  • This small amplitude oscillatory pressure will preferably be sufficient to continuously move the fluid mixture (and, for example, the cells within the liquid) continuously back and forth.
  • the oscillation frequency should be high enough such that the instantaneous fluid mixture velocity is sufficiently high to avoid deterioration of the mixture, while amplitude should be small enough such that there is little or no unintended net transportation into or out of the channel from adjacent reservoirs, reservoirs and intersecting channels.
  • a multiple capillary assembly 170 includes a microfluidic body or chip 172 mounted a polymer interface housing 174.
  • a plurality of capillaries 176 contain fluid introduction channels.
  • the capillary channels can be used to spontaneously inject fluids into the microfluidic network of chip 172 using capillary forces between the injected fluid and the capillary channels. Such spontaneous injection is sufficient to induce a pressure transient for measurement of hydrodynamic and/or electrokinetic flow.
  • Such flow measurements allow the derivation of information regarding the properties of the chip, microfluidic network, and/or fluids.
  • a simple chip 178 having a relatively straightforward microfluidic network may be used to understand the derivation of flow and/or chip properties from spontaneous injection.
  • the open end of capillary 176 will be placed in a fluid, typically by introducing the end of the capillary into a microtiter plate (or any other structure supporting one or more fluid test samples). This may be effected by moving the capillary 176 and chip 178 relative to the microtiter plate, by moving the microtiter plate relative to the capillary or by moving both structures relative to each other.
  • placing capillary 176 into a fluid results in spontaneous introduction of the fluid into the capillary channel.
  • a steady flow may then be provided along a channel coupling the capillary to the well.
  • a flow perturbation can be initiated at intersection 186 between the capillary channel and the microfluidic network at the time the capillary is withdrawn out from the well containing the introduced fluid.
  • This flow perturbation may, for example, comprise a change in composition of the flow progressing along channel 182 toward vacuum reservoir 180c. This change in composition may be sensed at a detection location 184 as, for example, a change in fluorescent intensity.
  • Similar flow perturbations might be induced by applying other pressure transients at intersection 186, for example, when capillary 176 is introduced into the spontaneously injected fluid, or by applying a change in pressure using a pressure modulation pump as described above, again changing the composition of the flow within channel 182.
  • progress of the perturbations may be detected.
  • a time delay between initiation of the perturbation and their respective detections at the detection point when combined with a known length of channel 182, can be used to determine a speed of the flow within the channel. From this actual, real-time speed, a variety of information regarding the fluid and/or network system may be determined.
  • a perturbation will be generated at a capillary intersection 186 coupling the capillary channel with the microfluidic network. Additionally, as the pressure perturbation will propagate throughout the microfluidic network, another flow perturbation may be simultaneously initiated at a second intersection 186a downstream of the sipper intersection 186. If we assume that fluid is flowing from reservoirs affixed to the microfluidic network toward a vacuum reservoir 180c, the pressure transient applied by spontaneous injection at capillary 176 will alter the mixtures occurring at each intersection.
  • the first signal 188a may be said to have occurred after a time delay of ⁇ t 1 , with this time being the time required for flow to propagate from the intersection immediately upstream of detector 184.
  • a similar time delay ⁇ t 2 will then be required for the flow to propagate from the second upstream intersection (186 in the simple network of Fig. 16A).
  • the various time delays can be used to determine the various fluid speeds between intersections.
  • this information can be used to determined contributions from branch channels to the flow volume, and the like, regardless of whether the flows throughout the microfluidic system are induced hydrodynamically, electrokinetically, electroosmotically, or the like.
  • capillary 176 may be dipped into and removed from a variety of fluids in a sequential series.
  • P indicates pressure
  • S 1 is a signal indicating a flow perturbation caused at a first intersection by spontaneous injection into the capillary
  • signals S 2 indicates a flow perturbation signal generated at a second intersection by the same spontaneous injection at the capillary.
  • a series of pressure transients 190 will be generated by capillary 176 when the capillary is, for example, dipped into and removed from a dye, followed by dipping of the capillary into a buffer solution, followed dipping of the capillary into a first test substance well, and the like.
  • This sequence of spontaneous injection events at capillary 176 may result in generation of a series of S 1 signals due to a series of flow perturbations at, for example, intersection 186a.
  • a series of second flow perturbation signals S 2 will also be generated at intersection 186, with detection of the second series following the first series by a time delay ⁇ t 2 which is dependent on the speed of fluid within the network channels.
  • the total signal S t measured at detector 184 will be a combination of this offset series of signals with the more immediate S 1 signals.
  • the composition of the overall flow arriving at the detector may vary significantly with the different materials introduced by capillary 176. Regardless, by properly identifying the time delays between signals, flows between the nodes of the microfluidic system may be calculated.
  • placing a detector 184a downstream of an electrode v 1 may facilitate measurements of electrically induced flow, such as electroosmotic flows induced by a differential voltage between V 1 and V 2 .
  • electrically induced flow such as electroosmotic flows induced by a differential voltage between V 1 and V 2 .
  • pressure perturbations will be initiated at the channel intersections, so that an initial signal may be generated at the detector from the downstream electrode V 1 , followed by another signal generated at the upstream electrode V 2 .
  • ⁇ t 1 as the time delay between these electrode intersections and ⁇ t 2 as the time delay for a subsequent signal generated by a reaction channel at intersection 186, and knowing the lengths of the channels ⁇ d 1 , ⁇ d 2 we can calculate the electroosmotic EO flow as follows:
  • Fig. 19 graphically illustrates data from a detector or sensor from which the time delays discussed above may be taken.
  • the multiple capillary assembly and simplified capillary networks of Figs. 15,16 and 16A are examples of microfluidic devices which might benefit from monitoring of pressure induced flow perturbations for analysis and/or control of flows, quality control, and the like. Additional examples of microfluidic structures which may benefit from these techniques are illustrated in Figs. 17A, 17B, 18A and 18B.
  • more complex microfluidic networks may include a plurality of capillary joints or intersections 192 and substrate wells or reservoirs 194, enzyme wells 196, wastewells 198, and the like.
  • One or more detection or sensor windows or locations 200 may be provided for monitoring of propagation of the flow perturbations.
  • the microfluidic assembly and network of Figs. 17A and 17B may be useful for multi-capillary fluorogenic assays.
  • a multi-capillary basic mobility-shift microfluidic assembly and network having similar structures is illustrated in Figs. 18A and 18B. This structure also includes a plurality of electrode wells 202 for applying voltages to the microfluidic network, as described above.

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CN110506204A (zh) * 2017-02-17 2019-11-26 生命技术公司 用于样品分析仪器的自动化质量控制及光谱误差校正
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